Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

Cell Res. 2012 Aug;22(8):1227-45. doi: 10.1038/cr.2012.82. Epub 2012 May 22.

Abstract

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • DNA Topoisomerases, Type I / metabolism
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • GATA2 Transcription Factor / genetics
  • GATA2 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras)
  • Pyrazines / pharmacology
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Topoisomerase I Inhibitors / pharmacology
  • Topotecan / pharmacology
  • Transcriptional Activation
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • CDC6 protein, human
  • Cell Cycle Proteins
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • KRAS protein, human
  • Nuclear Proteins
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins
  • Pyrazines
  • RNA, Small Interfering
  • Topoisomerase I Inhibitors
  • Deoxycytidine
  • Bortezomib
  • Topotecan
  • gemcitabine
  • Proteasome Endopeptidase Complex
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • DNA Topoisomerases, Type I